1. Field of the Invention
The present invention relates to novel synthetic intermediates for the production of carbapenem derivatives, which have excellent antimicrobial activity and a broad antimicrobial spectrum, and a process for the production thereof.
2. Related Art
Carbapenem derivatives have high antimicrobial activity and a broad excellent antimicrobial spectrum and thus have been energetically studied as a highly useful β-lactam agent.
In WO 02/42312, the present inventors have reported their finding that carbapenem derivatives having a 7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring, that is, compounds of formula (A), have high antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria including MRSA (methicillin resistant Staphylococcus aureus), PRSP (penicillin resistant Streptococcus pneumoniae), Haemophilus influenzae, and β-lactamase producing bacteria, and, at the same time, have high stability against DHP-1 (kidney dehydropeptidase-1). In this publication, a production process shown in scheme A below is disclosed as a production process of such derivatives.
wherein R1 represents a hydrogen atom or represents a protective group of hydroxyl; R2 represents a protective group of carboxyl; and L3 represents a leaving group.
According to this production process, the compound of formula (A) is produced by reacting a compound of formula (i) with a compound of formula (ii) in the presence of a palladium catalyst, a phosphine ligand, and an additive to give a compound of formula (iii), subsequently reacting the compound of formula (iii) with a compound of formula (iv) to give a compound of formula (v), and then deprotecting the compound of formula (v).
However, the compound of formula (ii) used in this process and reagents such as a trialkyltin chloride used for preparing this compound belong to organotin compounds and are known to be highly toxic. Further, the palladium catalyst and the phosphine ligand used in the reaction of the compound of formula (i) with the compound of formula (ii) are generally expensive. Therefore, a process which can produce the carbapenem derivatives of formula (A) in a highly safe and more cost-effective manner has been desired.